Our data indicate that hypercortisolism in depression and anorexia nervosa results from a defect at or above the hypothalamus, causing hypersecretion of CRH. These conclusions were based on studies evaluating pituitary-adrenal responses to ovine CRH, direct measurements of CRH in the CSF, and continuous administration of CRH and ACTH to volunteers. The finding that CSF CRH levels positively correlate with depression ratings in patients with anorexia nervosa further supports the idea that depression and anorexia nervosa share common pathophysiological features and may reside together within a large depressive disorder spectrum. Similar studies in Cushing's disease indicate that hypercortisolism in this disorder reflects a primary defect of the pituitary corticotroph cell. The differential pathophysiology of hypercortisolism in depression and Cushing's disease provides the context for the observation that less than 25% of a total of 65 patients with these illnesses show peak ACTH responses to CRH which overlap. The post-operative adrenal insufficiency in Cushing's disease reflects hyperresponsiveness of both the hypothalamic and pituitary components of the axis. Hence, such patients show a clear, but subnormal, response to a single bolus of ovine CRH, while repeated priming doses of CRH reactivate the pituitary-corticotroph cell. The latter finding indicates that the corticotroph, like the gonadotroph, requires priming of its hypothalamic releasing factor to function normally. In vitro hypothalamic cell culture studies show that norepinephrine, serotonin, and acetylcholine cause a dose-dependent release of CRH; conversely, GABA A and GABA B agonists, cortisol, and ACTH (but not CRH) each inhibit serotonin-induced CRH secretion in a dose-dependent fashion. In an effort to develop a quantifiable means of stress-mediated pituitary-adrenal activation, we have shown dose-dependent ACTH and cortisol responses to graded levels of exercise that correlate positively with the plasma lactate concentrations. Antagonism of glucocorticoid function with RU 486 enhances immune function, indicating that even basal glucocorticoid levels restrain the immune apparatus.